The past 5 years have seen dramatic growth in the evidence supporting vast IBD heterogeneity as well as in the variety of powerful approaches to decipher it. Better understanding of the commensal microenvironment and its relation to the now nearly 200 IBD associated genetic loci has added billions of additional variables and revealed many new biologic pathways. Fortunately, analytic methods that find relevant patterns in these massive data sets (big science), along with our ever more precise bench approaches (little science), including specialized in vivo models, stem cell directed human intestinal organoids (HIOs) and sophisticated in vitro technology, render conditioning parameters that can be even further refined by big science approaches. In this proposal, the program project (PPG) is reconfigured to make the best use of both approaches. The interactions and progress over the previous cycle led naturally to an exciting new structure, which takes aim at genetic influences on the host/environmental interface and their individual and combined contributions to severe IBD phenotypes. Our plan is to leverage the PPG's collective experience in multidirectional translation and merge our strengths in big and little science to define the relationship between genetic variation of the host and the commensal microenvironment and the consequential processes leading to severe forms of IBD. We hypothesize that distinguishing signatures of subtypes of severe IBD can be compiled based on an aggregate of genetic variation(s) and resultant gene expression profiles in single or interacting host pathobiologic pathways, in conjunction with metabotypic evidence reflecting alterations in metagenomic relationships between bacterial and/or fungal members of the commensal microenvironment. Elucidating the mechanism(s) of this biologic interface will require purposeful integration of big and little science. The 4 projects and two cores are conceived to approach this hypothesis as follows: Project 1 (McGovern) will generate innovative gene risk scores (GRS), then using a refined big science methodology will define the roles of multiple genes in specific pathways related to severe forms of IBD and to understand their interactions with components of the commensal microenvironment. Project 2 (Targan), deploying little science techniques, including a very novel approach using genotype-specific HIOs, addresses the relationship between TL1A and the microbiome, their individual and combined effects on Paneth cells, and how this interplay contributes to disease severity. Project 3 (Kronenberg), will examine the relationship of the Lt?R network (including TNFAF14/LIGHT) and its relationship to the intestinal microbiome in influencing mucosal inflammation. Project 4 (Underhill), will investigate the relationship between fungal communities and the immune system and their combined contribution to IBD. The engine that drives all of this research is the unique, large repository of samples and correlate genetic, tissue expression, serologic, immunologic and clinical metadata provided by Core B.